Catalpol alleviates glandular and pulmonary injury in primary Sjögren's syndrome via regulation of sphingolipid metabolism.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, pSS-related oral and ocular dryness is associated with depletion of yin and body fluids, while pulmonary involvement may reflect impaired lung moistening. Rehmannia glutinosa is traditionally used to nourish yin, generate fluids, and relieve dryness. Catalpol, its major iridoid glycoside, may provide a pharmacological basis for these traditional uses. AIM OF THE STUDY: This study investigated the protective effects of catalpol in experimental pSS and examined the involvement of KDSR-mediated sphingolipid metabolism. MATERIALS AND METHODS: An antigen-induced experimental Sjögren's syndrome (ESS) mouse model, interferon-γ-stimulated A253 cells, and transforming growth factor-β-stimulated NIH-3T3 fibroblasts were used. Pseudo-targeted sphingolipidomics, multi-cohort transcriptomic analysis, molecular docking, molecular dynamics simulation, cellular thermal shift assays, and KDSR knockdown were performed. RESULTS: Catalpol improved salivary secretion and reduced glandular inflammation and epithelial apoptosis in ESS mice. It also attenuated ESS-associated pulmonary inflammation and fibrosis-related changes and suppressed fibroblast activation. Integrated sphingolipidomic and transcriptomic analyses identified disease-associated KDSR upregulation and alterations in the sphinganine/3-ketodihydrosphingosine ratio. Molecular simulation and cellular thermal shift assays supported a potential interaction between catalpol and KDSR. Catalpol reduced KDSR expression and inhibited integrin/FAK/MYH9 signaling, whereas KDSR knockdown attenuated its protective effects in vitro. CONCLUSIONS: Catalpol ameliorated glandular dysfunction and pulmonary injury in experimental pSS. These effects were associated with KDSR-mediated sphingolipid metabolism and suppression of integrin/FAK/MYH9 signaling.
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